Cardiomyocytes

Structure

Cardiac muscle consists of interlacing bundles of cardiomyocytes (muscle cells). Like skeletal muscle it is striated with narrow dark and light bands, due to the parallel arrangement of actin and myosin filaments that extend from end to end of each myocyte. However, cardiomyocytes are narrower and much shorter than skeletal muscle cells, being about 0.02 mm wide and 0.1 mm long, and are more rectangular than smooth muscle cells, which are normally spindle-shaped.

They are often branched, and contain one nucleus but many mitochondria, which provide the energy required for contraction. A prominent and unique feature of cardiac muscle is the presence of irregularly-spaced dark bands between myocytes. These are known as intercalated discs, and are due to areas where the membranes of adjacent myocytes come very close together. From a mechanical standpoint, intercalated discs are the “glue” that enables contractile force to be transmitted from one cardiomyocyte to another. Force generated by the motor protein myosin in the A band thick filaments of cardiomyofibrils (about 2.5 μm long, 1 μm in diameter) is transmitted along the actin filaments in the I bands to the Z discs at the ends of the sarcomere (Fig.1) , and hence along adjacent myofibrils until the force reaches the intercalated discs membranes at ends of the cell (Fig.2). In contrast, the intercalated discs resemble giant Z disc, so it seems reasonable to expect that these two structures will contain proteins in common. But while intercalated discs provide the mechanism for force transmission and allow action potentials to pass across the 3-nm gap junctions (Fig. 3), they also have other functions including chemical communication.

They allow ions to pass across the narrow (3 nm) extracellular space, they allow cardiomyocytes to add new myofibrils, and they contain a wide range of special ion channels (Na, K, water, ATP, Ca ions), receptors (mechanoreceptors, virus receptors, death receptors) and enzymes (kinases, proteases).

Classically, the intercalated disc is described as containing three known functional “zones”: (1) the fascia adherens, (2) desmosomes and (3) gap junctions (Fig. 3). More recently, a new region, the “transitional junction” was described (Bennett et al 2006) at the perimeter of fascia adherens. It is considered to be a spectrin-rich site where sarcomeres can be added to myofibrils during growth (hypertrophy) and development.

Ø Fascia adherens: The fascia adherens junction transmits force between coupled cells. It provides an anchor for myofibrils where thick myosin filaments and actin-thin filaments connect with the fascia adherens proteins that in turn anchor them to the intercalated disc membrane (i.e. the last Z disc of the cell). It contains the transmembrane the catenin (CTNN) proteins that connect the cadherins (CDH) to the sarcomeres, forming an intercellular contact. Consistent with the notion that the intercalated disc is a modified myofibrillar Z disc, α-actinin (ACTN) is present (Fig. 2). Of the 70 proteins reported in the literature, 24 are confirmed by HPA antibodies on their web site and a further 18 proteins or protein isoforms were found on the HPA site, but had not been reported previously. Currently, there are more than 6,000 HPA antibodies available, but this number increases by about 20–300 per month.

Ø Transitional junction: A report by Bennett et al. (2006) defined a new functional subcellular domain at the intercalated disc. Where the myofibrils insert at the fasica adherens, the plasma membrane is extensively folded and convoluted. This new junction is located at the interfibrillary region between the myofibrillar thin filaments and the intercalated disc. Using immunofluorescence and immunogold electron microscopy, they found that the junction was rich in spectrin, a membrane-bound protein that binds to filamentous actin (α-actinin, titin) to produce a robust force-resistant network between cells (Fig. 1).

Ø Gap junctions: The third functional zone along the intercalated discs is the gap junction, which is also known as the communicating junction (Gutstein et al 2003). Here, the normal gap between adjacent cardiomyocytes narrows from about 25 nm to about 3 nm. This junction provides electrical continuity using ion channels (connexons) that allow an action potential to propagate rapidly to several adjacent cardiomyocytes. In intercalated discs IC, connexons consist of six connexins (usually Cx43 and Cx40) that allow ions and small molecules to freely move across the narrow gap (Fig. 2). The connexin hexamers on one CM are exactly aligned to the corresponding connexion in the adjacent membrane, thus forming a pore. Thus, this specialised region of the ICD provides both electrical continuity and chemical communication between cardiomyocytes.